The present invention is directed to glycopeptides and is directed in particular to modifications of A82846B and its NDISACC variations. In the claimed compounds, the original N1 amino acid, N-methyl-D-leucine, has been removed and replaced with an acyl group or with an acyl group derived from an alternate xcex1-amino acid.
The present invention is directed to compounds of the formula 
where in R1 represents
alkanoyl of C2-C10 which is unsubstituted, or which is substituted by a phenyl, or which is substituted on other than the xcex1-carbon atom by an amino or protected amino group;
benzoyl or substituted benzoyl bearing one or two substituents each of which is independently halo, loweralkyl of C1-C4, loweralkoxy of C1-C4 or phenyl;
an acyl derived from an xcex1-amino acid or an acyl derived from a protected xcex1-amino acid, said xcex1-amino acid being selected from the group consisting of:
alanine,
arginine,
asparagine,
aspartic acid,
cysteine,
glutamic acid,
glutamine,
glycine,
histidine,
isoleucine,
leucine,
lysine,
methionine,
3-phenylalanine,
3-(p-chlorophenyl) alanine,
proline,
serine,
threonine,
tryptophan and valine,
in either D- or L-form; or
an acyl derived from an xcex1-amino acid as defined above which bears on the amine a substituent which is alkyl of C1-C10, benzyl, phenylbenzyl, or p-chlorobenzyl, with the proviso that the acyl derived from N-methyl-D-leucine is excluded;
R2 represents hydrogen, or epivancosaminyl of the formula 
wherein R2a represents hydrogen or xe2x80x94CH2xe2x80x94R3; and R3 represents hydrogen, alkyl of C1-C11, alkyl of C1-C11-R4, or R4-(linker(0 or 1)-R4)o or 1,
wherein each R4 is independently phenyl or phenyl substituted by one or two substituents, each of which is independently halo, loweralkyl of C1-C8, loweralkoxy of C1-C8, loweralkylthio of C1-C4, or trifluoromethyl, and xe2x80x9clinkerxe2x80x9d is xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, or xe2x80x94Oxe2x80x94(CH2)nxe2x80x94 wherein n is 1-3; and the pharmaceutically acceptable salts thereof.
When R1 represents alkanoyl of C2-C10, it can be a straight-chain alkanoyl, or it can be an alkanoyl which is branched to any degree. Likewise, when R3 represents alkyl of C1-C11, it can be straight-chain or branched.
The compounds of the present invention are prepared from the corresponding xe2x80x9cA82846B hexapeptidesxe2x80x9d of the formula: 
wherein R2 is as defined above. These xe2x80x9cA82846B hexapeptidesxe2x80x9d are so called because the normal N1 amino acid N-methyl-D-leucine, has been removed, reducing the number of amino acids in the parent glycopeptide from seven to six.
The compounds of the present invention are prepared by reacting an A82846B hexapeptide with an activated ester of an alkanoic acid of the desired acyl group R1. By xe2x80x9cactivated esterxe2x80x9d is meant an ester which renders the carboxyl function more reactive to coupling with the amine of the A82846B hexapeptide. The reaction of the A82846B hexapeptide and activated ester is carried out in an organic solvent, suitably a polar solvent such as dimethylformamide, dimethyl sulfoxide, or a mixture of dimethylformamide and dimethyl sulfoxide. The reaction proceeds under temperatures of a wide range, such as 250 to 100xc2x0 C., but is preferably carried out at temperatures of about 25 to 35xc2x0 C. Some of the desired product is produced shortly upon contacting the reactants, but higher yields are obtained with reaction times of from about 1 to about 24 hours, oftentimes from about 1 to about 5 hours. Isolation and purification are carried out under conventional procedures.
The starting A82846B hexapeptides are themselves synthesized from the parent glycopeptides: 
wherein R2a is as defined above. This synthesis is by the xe2x80x9cEdman degradationxe2x80x9d, a two-step process for the cleavage of the N-terminal residue of a peptide or protein. The above parent glycopeptide is first reacted with an isothiocyanate of the formula SCN-R5, to obtain an intermediate NLEU -(thiocarbamoyl)-A82846B compound of the formula 
In the foregoing formula, R5 represents alkyl of C1-C10, phenyl, naphthyl, or phenyl substituted by one or two substituents, each of which is independently halo, loweralkyl of C1-C4, loweralkoxy of C1-C4, benzyloxy, nitro, or 
xe2x80x83wherein each R6 is independently loweralkyl of C1-C4.
This reaction is conveniently carried out in water with pyridine, at a temperature of 25xc2x0-30xc2x0 C., employing a slight excess of the isothiocyanate reactant. The NLEU-(thiocarbamoyl)A82846B intermediate can be separated in conventional manner or can be employed after removal of reaction solvent in the second step of the Edman degradation.
In the second step, the NLEU-(thiocarbamoyl)A82846B is reacted with an organic acid, preferably trifluoroacetic acid, in a non-polar solvent such a dichloromethane. The reaction proceeds at temperatures of from 0xc2x0 C. to 35xc2x0 C. but is preferably carried out at temperatures of from 0xc2x0 C. to 25xc2x0 C. The reaction is generally complete in several hours. The resulting hexapeptide product is separated and purified if desired in conventional procedures.
The second step of the Edman degradation can in some instances result in loss of the disaccharide epivancosamine. Longer reaction times can be used to obtain the desepivancosaminyl compound (R2=hydrogen).
Other variations at the disaccharide position of the molecule can be obtained in conventional procedures. As described above, the Edman degradation and subsequent acylation can be carried out with the naturally-occurring disaccharide (R2=epivancosaminyl with R2a=H) or with a disaccharide derivative (R2=epivancosaminyl with R2a=CH2xe2x80x94R3). This approach to synthesis of the present compounds is illustrated by the preparations below of Examples 12 and 26. However, it is also possible to prepare those claimed compounds with a disaccharide derivative (R2=epivancosaminyl with R2a=xe2x80x94CH2xe2x80x94R3) by first conducting the Edman degradation and subsequent acylation on A82846B, with its naturally occurring R2=epivancosaminyl, and thereafter introducing the desired epivancosaminyl substituent xe2x80x94CH2xe2x80x94R3. This is illustrated by Examples 34 and 35.
Whether the xe2x80x94CH2xe2x80x94R3 substituent is introduced prior to Edman degradation and acylation, or after, the same conventional process is used. In this process, the substrate compound is reductively alkylated with the aldehyde suitable to introduce the desired xe2x80x94CH2xe2x80x94R3 group. This process is taught in various references, see U.S. Pat. No. 5,591,714, and EPO 667,353.
The compounds of the present invention readily form salts, which can be prepared in conventional manner.